The present invention relates to methods and compositions for medical treatment; and more particularly, this invention relates to methods and compositions for the treatment and prophylaxis of calcium renal stones.
Formation of stones within the urinary tract (clinically termed nephrolithiasis) represents a common health disorder. In the United States an estimated 5-10% of the population will develop urinary stones in their lifetime. Of these stones virtually all originate in the kidneys, while bladder stones are rarely encountered except in association with a foreign body. Nephrolithiasis, while usually not fatal, causes considerable suffering, morbidity and loss of work. Often it is a disease which recurs throughout a patient's lifetime.
The medical profession has become increasingly aware that recurrent formation of renal stones may be prevented by a variety of medical interventions in a significant number of patients at risk for nephrolithiasis. However, many treatment programs are used indiscriminately without regard for the particular cause for stone formation. For example, stones of renal origin may be broadly categorized on the basis of their chemical composition as those containing calcium, and those which do not. Calcareous renal stones account for 80-90% of stones, and are principally composed of calcium oxalate (dihydrate or monohydrate) and calcium phosphate (apatite or rarely brushite and whitlockite). Further, calcareous renal stones can be subdivided into physiological pathogenesis, for example hypercalciuria, hyperuricosuria, hyperoxaluria and hypocitraturia. Non-calcareous renal stones include those containing uric acid, cystine, or magnesium ammonium phosphate (struvite).
Notwithstanding the various etiologies attributed to renal stone formation, treatments have generally been randomly selected. Thus, orthophosphate and thiazide have been used in various forms of hypercalciuric as well as in normo-calciuric states, and allopurinol has been used in hyperuricosuria as well as in normouricosuria. With respect to non-calcareous renal stones, specifically uric acid lithiasis, an improved treatment program has virtually eradicated the incidence of this disease state. Unfortunately treatments effective for uric acid stones, specifically administration of sodium citrate and sodium bicarbonate, appear to potentiate formation of calcium stones, (see e.g. Sakhaee, Nicar, Hill, and Pak, "Contrasting Effects of Potassium Citrate and Sodium Citrate Therapies on Urinary Chemistries and Crystallization of Stone-Forming Salts", Kidney International, (V 24, pp. 348-351 (1983)), incorporated by reference herein).
Coincident with the recognition of the above, the present applicant advocates a more selective approach, in which specific treatments are chosen for particular causes of stone formation. This approach recognizes the heterogeneity of pathogenic background for nephrolithiasis and tailors treatment programs to ameliorate, correct or prevent the specific underlying derangement.
The teachings of Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al. (U.S. Pat. No. 4,405,596) are related to the processes of the present invention and are incorporated by reference herein. These U.S. patents involve the administration of an alkali-acting substance, prototypically sodium bicarbonate, to increase plasma bicarbonate level and induce alkalotic volume contraction. Kopp et al. (U.S. Pat. No. 4,289,750) state that although alkaline-acting substances other than sodium bicarbonate may be used, the alkaline-acting substance "would be adapted to release sodium and bicarbonate ions." (col 5, lines 40-44). Kopp et al. (U.S. Pat. No. 4,289,750) further indicate that an appropriate dose regimen of alkali-acting substance would raise blood bicarbonate levels by a 4 to 5 mEq/l base excess value. As shown in Pak et al. (J. of Urol. vol. 134, pp 11-19, see Table 5 (1985)), incorporated by reference herein, an effective dose regimen of potassium citrate did not raise serum bicarbonate or CO.sub.2 levels to more than a fraction of this extent. It is also mentioned in Kopp et al. (U.S. Pat. No. 4,289,750) that its oral preparations "--are highly effective in increasing urine volume when administered at correct minimum dosage levels--" (col. 7, lines 63.gtoreq.65). As shown later herein, particularly in Table I, administration of effective levels of potassium citrate induces but a minor and statistically non-significant increase in urine volume.
Both Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al. (U.S. Pat. No. 4,405,596) focus primarily upon patients with altered function or renal insufficiency. These clinical syndromes, particularly renal insufficiency, are contraindicative of potassium citrate therapy according to the processes of the present invention because the potassium citrate-based therapy might lead to hyperkalemia.
The alkaline-acting substances of Kopp et al. and Helbig et al. may be combined with additional active agents. Kopp et al. (U.S. Pat. No. 4,289,750) state that potassemia (sic) may be corrected by including a potassium compound such as potassium chloride, potassium bicarbonate or potassium citrate in the oral preparations of that invention. This reference further states that prevention of kidney stone formation or elimination of kidney stones may be encouraged by "inclusion in oral preparations of substances such as alkali or alkali earth metal citrates, or inclusion of urea itself". Thus one condition (potassemia) may be corrected, it is taught, by addition of a salt such as potassium citrate. Another condition (kidney stone presence or formation), it is taught, may be alleviated by the creation of a state of alkalotic volume contraction with increased urine volume and then adding substances such an alkali or alkali earth metal citrate. There is no indication in Kopp et al. (U.S. Pat. No. 4,289,750) that, as described elsewhere herein, sodium citrate encourages calcareous kidney stone formation. Nor is there any indication in Kopp et al., that specifically potassium citrate, on the contrary, alleviates this condition, even in the absence of alkalotic volume contraction.
Helbig et al. (U.S. Pat. No. 4,405,596) state that, in their preparations containing alkaline-acting agents, cations other than sodium may be suitable but that sodium is preferred. It is indicated in Helbig et al. (U.S. Pat. No. 4,405,596), a continuation-in-part of Kopp et al. (U.S. Pat. No. 4,289,750), that alkali or alkali earth metal salts of citric acid may be used for prophylaxis and therapy of kidney stones. These salts are directed to be administered as `additional active agents` in conjunction with an alkaline-acting substance (col 1, lines 35-48). Additionally, Helbig et al. (U.S. Pat. No. 4,405,596) state that "the novel and essential characteristic of the oral dosage form of the invention is that resorbable bicarbonate ions are formed or released only in the intestine of a subject" (col. 5 lines 36-39). This characteristic distinguished their `alkaline-acting` agent from other substances such as metallic citrates which do not intestinally release resorbable bicarbonate. Specific metallic citrates mentioned included hexapotassium-hexasodium-heptacitrate-hydrate- and hexacalcium-hexasodium-heptacitrate-hydrate-complexes. As it may be seen from these descriptions, Kopp et al. (U.S. Pat. No. 4,289,750) and Helbig et al. (U.S. Pat. No. 4,405,596) provide no guidance to the discoveries inherent in the present invention involving the use of potassium citrate free of substantial sodium and bicarbonate-releasing capability in intestinal lumen to effect a new cure for calcareous kidney stones.
The results of the present invention described herein clearly demonstrate that the administration of potassium citrate (but not sodium citrate), unaccompanied by alkali-acting substances releasing intestinal bicarbonate, is an effective treatment for calcareous kidney stones. Thus, sodium citrate is ineffective for treatment of kidney stones and sodium bicarbonate or any other sodium salt in combination with potassium citrate would detract from the therapeutic effectiveness of the potassium citrate by converting the potassium citrate to sodium citrate by equilibrium and ionic interchange.
In an earlier study, Rudman et al.(N. Eng. J. Med. Vol. 303, pp 657-661 (1980)) described the oral administration of a "citrate punch" comprising sodium citrate and citric acid to patients with hypocitraturia. This reference showed no increase in urinary citrate when patients were treated only with the "citrate punch". It was found that the hypocitraturia was corrected only when the "citrate punch" administration was accompanied by an intramuscular injection of magnesium sulfate. Although Rudman et al. acknowledged that hypocitraturia may result from hypokalemia or acidosis, no suggestion of using potassium citrate for treatment of calcareous kidney stones was made.